title: Immunomodulatory and toxic effects of free and liposome-encapsulated tumor necrosis factor alpha in rats.
abstract: Tumor necrosis factor alpha has potent immunomodulatory and antitumor activity, but its therapeutic applications may be limited by its significant host toxicity. We showed that liposome-encapsulated recombinant human tumor necrosis factor alpha (rHuTNF-alpha) retained full anticellular activity in vitro. We then assessed the immunomodulatory and toxic effects of two different doses of i.v. free or liposome-encapsulated rHuTNF-alpha in normal rats. Both free and liposome-encapsulated rHuTNF-alpha significantly enhanced alveolar macrophage- and blood monocyte-mediated interleukin 1 release and tumor cell lysis, as well as natural killer cell cytotoxicity, when compared to buffer-treated controls. However, administration of rHuTNF-alpha in liposomes substantially reduced tumor necrosis factor alpha-mediated toxicity. Animals receiving liposome-encapsulated rHuTNF-alpha showed significantly less tissue injury, gastric retention, and circulating leukocyte shifts than animals receiving free rHuTNF-alpha. In addition, liposome-based delivery significantly increased lung and liver uptake of rHuTNF-alpha. Therefore, liposome-encapsulated rHuTNF-alpha retains immunomodulatory activity, significantly reduces toxic inflammatory effects, and may allow targeting of tumor necrosis factor alpha to selected organs after i.v. administration.
authors.affiliation: Cancer Research Institute, University of California, San Francisco 94143.
authors.forename: R J
authors.initials: RJ
authors.lastname: Debs
authors.forename: H J
authors.initials: HJ
authors.lastname: Fuchs
authors.forename: R
authors.initials: R
authors.lastname: Philip
authors.forename: E N
authors.initials: EN
authors.lastname: Brunette
authors.forename: N
authors.initials: N
authors.lastname: Düzgüneş
authors.forename: J E
authors.initials: JE
authors.lastname: Shellito
authors.forename: D
authors.initials: D
authors.lastname: Liggitt
authors.forename: J R
authors.initials: JR
authors.lastname: Patton
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D004337:Drug Carriers; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008081:Liposomes; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha